The proper functioning of the mature visual system depends upon experience-dependent refinement of cortical circuitry during early postnatal development. Visual deprivation during this early critical period (CP) can lead to loss of visual responsiveness to the deprived eye (amblyopia). Despite decades of research it is still unclear which cellular plasticity mechanism(s) contribute to this loss of visual responsiveness, and by extension are required for the normal development of visual function. For example, long-term depression (LTD) of cortical excitatory synapses has been suggested to be necessary and sufficient for loss of visual responsiveness following MD, while other studies have raised the possibility that potentiation of inhibition plays a critical role in this process. Recently the maturation of inhibition from fast-spiking GABAergic basket cells (FS cells) has been implicated in the regulation of CP onset, but why mature inhibition is necessary for CP plasticity is still unknown. During the past 2 funding periods we found that monocular deprivation (MD) during the rodent CP dramatically potentiates inhibitory transmission at FS synapses onto star pyramidal neurons (SP, the major excitatory cell type within L4 of rodent V1), by inducing a novel form of long-term potentiation of inhibition (LTPi) at this synapse. Further, LTPi is developmentally regulated, turns on coincidently with the opening of the CP, and manipulations that delay or advance the CP also delay or advance the ability of FS synapses to express LTPi. In this proposal we wish to test the central hypothesis that LTPi plays a critical role in the lossof visual responsiveness induced by visual deprivation, so that FS cells initiate the CP by gaining the ability to express LTPi. To this end we will exploit our mechanistic understanding of LTPi to block its induction in vivo, and determine the role LTPi plays in the cortical response to monocular deprivation (MD). Further, we will evaluate the relative importance of LTD and LTPi in MD-induced loss of visual responsiveness within L4, and ask whether these two forms of plasticity are induced in a synergistic manner during MD. We will combine in vivo and in vitro electrophysiology, viral-mediated gene transfer, and optogenetics to achieve these goals. These experiments will settle a long-standing debate about the mechanisms underlying amblyopia, and have the potential to radically alter our view of the cellular underpinnings of CP plasticity. ) PUBLIC HEALTH RELEVANCE: Amblyopia, or reduced vision due to the effects of early abnormal visual experience, affects approximately 3% of the human population. Designing effective treatments requires an understanding of the cellular and molecular mechanisms that underlie this process, but despite decades of work the synaptic plasticity mechanisms that underlie vision loss due to visual deprivation during developmental sensitive periods are still intensely debated. The experiments in this proposal will definitively establish the relative roles f these two forms of plasticity, and have the potential to suggest new avenues of treatment for amblyopia.